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Regulation of Steroidogenic Genes by Insulin-Like Growth Factor-1 and Follicle-Stimulating Hormone: Differential Responses of Cytochrome P450 Side-Chain Cleavage, Steroidogenic Acute Regulatory Protein, and 3ß-Hydroxysteroid Dehydrogenase/Isomerase in Rat Granulosa Cells¹

^a Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

The present study sought to characterize the concerted action of FSH and insulin-like growth factor-1 (IGF-1) on functional differentiation of prepubertal rat ovarian granulosa cells in culture. To this end, we examined the regulation of three key genes encoding pivotal proteins required for progesterone biosynthesis, namely, side-chain cleavage cytochrome P450 (P450_scc), steroidogenic acute regulatory (StAR) protein, and 3ß-hydroxysteroid dehydrogenase/isomerase (3ß-HSD). Time-dependent expression profiles showed that P450_scc, StAR, and 3ß-HSD gene products accumulate in chronic, acute, and constitutive patterns, respectively. Each of these genes responded to FSH and/or IGF-1 in a characteristic manner: A synergistic action of IGF-1 was indispensable for FSH induction of P450_scc mRNA and protein; IGF-1 did not affect FSH-mediated upregulation of StAR products; and IGF-1 alone was enough to promote expression of 3ß-HSD. The responsiveness of the genes to IGF-1 correlated well with their apparent susceptibility to the inhibitory impact of tyrphostin AG18, a potent inhibitor of protein tyrosine kinase receptors. Thus, IGF-1-dependent P450_scc and 3ß-HSD expression was completely arrested in the presence of AG18, whereas StAR expression was unaffected in the presence of tyrphostin. These findings suggest that FSH/cAMP signaling and IGF-1/tyrosine phosphorylation events are interwoven in rat ovarian cells undergoing functional differentiation. We also sought the mechanism of IGF-1 synergy with FSH. In this regard, our studies were unable to demonstrate a stabilizing effect of IGF-1 on P450_scc mRNA, nor could IGF-1 augment FSH-induced transcription examined using a proximal region of the P450_scc promoter (-379/+6). Thus, the mechanism of IGF-1 and FSH synergy remains enigmatic and provides a major challenge for future studies.

First decision: 18 December 2001.

¹ Supported by the United States-Israel Binational Sciences Foundation Grant 1999315.

² Correspondence. FAX: 972 2 658 6448; orly{at}vms.huji.ac.il

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